Free Access Articles
Origins of mosaicism and criteria for the transfer of mosaic embryos
Blastocysts classified as mosaic by preimplamtation genetic testing for aneuploidy (PGT-A) [usually through array comparative genomic hybridization (aCGH) or next-generation sequencing (NGS)] have been reported to implant less frequently and miscarry more frequently than embryos classified as euploid, but still be able to produce chromosomally normal and viable pregnancies (Fragouli et al., 2017; Greco et al., 2015; Munné et al., 2017; Spinella et al., 2018). As such, the Preimplantation Genetic Diagnosis International Society (PGDIS), Controversies in Preconception, Preimplantation and Prenatal Genetic Diagnosis (CoGEN) and others (Munné et al., 2016) have recommended that care providers prioritize euploid embryos over mosaic embryos for transfer and only consider mosaics for replacement when no euploid embryos are available.Imaging the ovary
Using mainly histological analyses of fixed ovarian tissues and ultrasound imaging of ovaries in vivo, earlier imaging studies have established the basic framework of ovarian folliculogenesis as well as luteal formation and regression. The ovary contains individual follicles as functional structures, together with corpora lutea, interstitial tissues, innermost medulla and the outmost layer of the surface epithelium. Most of the 800,000 primordial follicles found at birth in human females remain at the dormant stage.Chief editor's 2017 annual report
2017 was an exciting and rewarding year for RBM Online, as it continued to provide cutting-edge information regarding basic, translational and clinical aspects of infertility and related areas of reproductive health. Among the successes, most notably the impact factor reached a value well above 3 for the first time in the journal's history (Figure 1), placing it in the first quartile of all journals published in the categories ‘Obstetrics and Gynecology’ and ‘Reproductive Biology’.Can time-lapse parameters predict embryo ploidy? A systematic review
Embryo morphology assessment performs relatively poorly in predicting implantation. Embryo aneuploidy screening (PGS) has recently improved, but its clinical value is still debated, and the development of a cheap non-invasive method for the assessment of embryo ploidy status is a highly desirable goal. The growing implementation of time-lapse devices led some teams to test the effectiveness of morphokinetic parameters as predictors of embryo ploidy, with conflicting results. The aim of this study was to conduct a comprehensive review of the literature on the predictive value of morphokinetic parameters for embryo ploidy status.A demographic projection of the contribution of assisted reproductive technologies to world population growth
Enormous unmet needs for infertility treatment exist because access to assisted reproductive technologies is demographically skewed. Since the first IVF baby in 1978, the number of people conceived by reproductive technology has grown much faster than expected, reaching several million today and rapidly approaching 0.1% of the total world population. As more patients build families, and their children in turn become parents, the number owing their existence to assisted reproductive technologies, either directly or indirectly, will expand tremendously in future decades, but no attempts have been made hitherto to project the magnitude.Multiple pregnancies achieved with IVF/ICSI and risk of specific congenital malformations: a meta-analysis of cohort studies
Studies comparing risk of specific congenital malformations (CM) between multiple pregnancies resulting from IVF/intracytoplasmic sperm injection (ICSI) and those conceived naturally report conflicting results; furthermore, there is a lack of a complete overview. This meta-analysis aimed to address which types of CM are increased in IVF/ICSI multiple pregnancies compared with those conceived naturally. All studies testing the association between IVF/ICSI multiple pregnancies and specific CM identified in various databases were considered.Effect of male body mass index on assisted reproduction treatment outcome: an updated systematic review and meta-analysis
Men with a body mass index (BMI) of 30 or over are more likely to have reduced fertility and fecundity rates. This systematic review and meta-analysis evaluated the effect of male BMI on IVF and intracytoplasmic sperm injection (ICSI) outcome. An electronic search for published literature was conducted in MEDLINE and EMBASE between 1966 and November 2016. Outcome measures were clinical pregnancy rates (CPR) and live birth rates (LBR) per IVF or ICSI cycle. Eleven studies were identified, including 14,372 cycles; nine reported CPR and seven reported LBR.Follicular flushing in patients with poor ovarian response: a systematic review and meta-analysis
A systematic literature review and meta-analysis was conducted to evaluate the effect of follicular flushing on clinical outcomes (primary outcome: mean number of cumulus–oocyte–complexes [COC]) in poor-response IVF patients). The bibliographic databases OvidMedline (includes Pubmed), Cochrane Library and Web of Science were searched electronically for randomized controlled trials (RCT) comparing follicular flushing with no flushing. Three RCT with a total of 210 patients could be included. The mean number of COC did not increase with flushing (weighted mean difference: −0.45 COC, 95% CI −1.14 to 0.25, I2 = 70%; P = 0.21; three RCT, n = 210).A search for molecular mechanisms underlying male idiopathic infertility
Infertility affects approximately 15% of the couples wanting to conceive. In 30 − 40% of the cases the aetiology of male infertility remains unknown and is called idiopathic male infertility. When assisted reproductive technologies are used to obtain pregnancy, an adequate (epi)genetic diagnosis of male infertility is of major importance to evaluate if a genetic abnormality will be transmitted to the offspring. In addition, there is need for better diagnostic seminal biomarkers to assess the success rates of these assisted reproductive technologies.Surging ahead
2017 was a very successful year for RBMOnline, most notably with the announcement of an Impact Factor of 3.249, the highest yet achieved by the journal since its inclusion in the ranking nearly 10 years ago, and matched by improvements in other ranking metrics such as CiteScore, Article Influence and SNIP. This outcome reflects the increased quality of the papers published in the journal and places it in sixth position in the ranking of reproductive biology titles. As part of the continuing development of the journal, we welcomed Richard Anderson to the team of editors (Anderson, 2017), joining Mina Alikani, Juan Garcia Velasco and Martin Johnson, and allowing the Chief Editor more time to focus on strategic considerations.Role of Withania somnifera (Ashwagandha) in the management of male infertility
To manage male infertility caused by hormonal imbalance, infections and other predicaments, multifarious treatment strategies are emerging worldwide. Contemporary treatments, such as assisted reproductive techniques, are costly with low success rates of only 10–30%; however, herbal remedies are gaining more attention as an alternative or supplementary therapeutic modality for male infertility. The beneficial effects induced by oral intake of the roots of a small evergreen shrub, Withania sominifera (Ashwagandha) on semen quality of infertile men have previously been studied.Dignity again
Two recent contributions to this journal discuss a challenge to Stanford's time-lapse embryo monitoring patent, currently before the European Patent Office (EPO). Sterckx, Cockbain and Pennings (2017) would like to keep the morphokinetics of embryo division in the public domain; they argue that time-lapse monitoring (TLM) is a diagnostic method in the sense of European patent law and therefore unpatentable. In response, Pearce (2017) suggests that the jurisprudence of the EPO unambiguously says that TLM is not a diagnostic method.Risk of pelvic inflammatory disease after intrauterine insemination: a systematic review
The aim of this study was to ascertain the incidence of pelvic inflammatory disease (PID) after intrauterine insemination (IUI). A systematic review was conducted using three different approaches: a search of IUI registries; a search of published meta-analyses; and a search of prospective randomized trials. Search terms were ‘IUI’, ‘complications’, ‘infection’ and ‘PID’. Two IUI registers were identified that met the inclusion criteria, totalling 365,874 cycles, with 57 PID cases being reported.The uterine fibroid/myoma tumour: analysis of the global research architecture using density-equalizing mapping
Uterine fibroids can severely impact a woman’s quality of life, result in significant morbidity and are a leading indication for hysterectomy. Many aspects of the disease remain largely obscure. Despite these knowledge gaps, no detailed maps of the global fibroid research architecture have yet been generated. This study used the NewQIS approach to assess worldwide research productivity, encompassing numerous aspects of the scientific output, quality and socioeconomic features. Regression analysis indicated an increase in fibroid research activity in the investigated time periods.Progress in the diagnosis and management of adolescent endometriosis: an opinion
Until recently, adolescent endometriosis has been considered a rare, often transient, condition not particularly serious for the young patient. Against this background, and not without disagreement by some, we have pointed out that early onset endometriosis (EOE) may at times be severe, necessitating quick diagnosis and proper treatment (Brosens et al., 2013b, 2014). To substantiate this viewpoint, we carefully searched published research, including some early paediatric research, and identified peritoneal reflux from neonatal uterine bleeding (NUB) occurring in 3–5% of female neonates, as a biologically plausible and likely cause of EOE (Brosens and Benagiano, 2013, 2016; Brosens et al., 2013a; Gargett et al., 2014).Insights from clinical experience in treating IVF poor responders
‘Poor responders’ is a term used to describe a subpopulation of IVF patients who do not respond well to ovarian stimulation with gonadotrophins. While there is no standard definition of a poor responder, these patients tend to be of advanced maternal age (≥40 years), have a history of poor ovarian response with conventional stimulation protocols, and/or have low ovarian reserve. Despite the heterogeneity of this patient group, there are characteristics and needs common to many poor responders that can be addressed through a holistic approach.Comments on the ESHRE recommendations for the treatment of minimal endometriosis in infertile women
According to ESHRE recommendations for women with stage I/II endometriosis, if a decision is made to proceed to laparoscopy then operative laparoscopy (excision or ablation of the endometriotic lesions) should be performed rather than only diagnostic laparoscopy, to increase ongoing pregnancy rates. Also, for infertile women with stage I/II endometriosis doctors may consider complete surgical removal of endometriosis to improve live birth rate prior to assisted reproductive treatment. This last recommendation is not well established.Extragonadal primordial germ cells or placental progenitor cells?
Primordial germ cells (PGCs), the precursors of the gametes, are now claimed to segregate within the extra-embryonic tissues of three species of placental mammals. In this brief Commentary, I raise the question of whether the so-called PGCs are not PGCs at all, but rather, progenitor cells that build the fetal–placental interface in Placentalia.GnRHa trigger and luteal coasting: a new approach for the ovarian hyperstimulation syndrome high-risk patient?
Final oocyte maturation using gonadotrophin-releasing hormone agonist (GnRHa) is increasingly common as it almost eliminates the risk of developing ovarian hyperstimulation syndrome (OHSS) in high-responder patients. The first studies using this approach showed a poor reproductive outcome when only vaginal progesterone was used as luteal phase support, due to the luteolysis that will develop as a result of LH withdrawal. Timely luteal administration of human chorionic gonadotrophin (HCG) will counterbalance the low LH concentrations and therefore maintain progesterone production from the corpora lutea, however, some patients with a high number of follicles will develop OHSS using this approach.Perinatal outcomes after stimulated versus natural cycle IVF: a systematic review and meta-analysis
Pregnancies resulting from assisted reproductive techniques are at higher risk of adverse perinatal outcomes compared with spontaneous conceptions. Underlying infertility and IVF procedures have been linked to adverse perinatal outcomes. It is important to know if ovarian stimulation influences perinatal outcomes after IVF. A systematic search for relevant studies was conducted up to November 2016 on the following databases: PubMed, EMBASE, DARE and Cochrane Central Register of Controlled Trials.A clinical assay for reactive oxygen species – ready for primetime?
Reactive oxygen species (ROS) have been demonstrated to have damaging effects on human sperm function. The measurement of ROS as an adjunct to traditional semen analysis has clinical relevance as part of the diagnosis of male infertility. The assay best suited to the clinical laboratory environment for detecting ROS generation remains somewhat controversial. A recent report on a multicenter study evaluating the reduction of nitroblue tetrazolium (NBT) to formazan precipitate as an indirect reporter of ROS-generating activity in spermatozoa, seminal plasma and semen has received a critique raising questions as to the sensitivity and specificity of the assay for detecting ROS.Chimeras intended for human gamete production: an ethical alternative?
Human eggs for basic, fertility and stem-cell research are in short supply. Many experiments that require their use cannot be carried out at present, and, therefore, the benefits that could emerge from these are either delayed or never materialise. This state of affairs is problematic for scientists and patients worldwide, and it is a matter that needs our attention. Recent advances in chimera research have opened the possibility of creating human/non-human animal chimeras intended for human gamete production (chimeras-IHGP).Human-animal chimeras: circumventing rather than discussing ethical concerns comes at a price
This issue of RBMOnline features a highly interesting paper on chimeras intended for human gamete production by philosopher César Palacios-González (2017). The paper breaks new ground by linking two ethically charged scientific developments. Whilst several groups are aiming to create stem cell-derived gametes through tissue culture in the laboratory (Hendriks et al., 2015), others are working on interspecies chimeras as a possible future route to obtaining human stem cell-derived organs from animals, both for research and for transplantation purposes.Paving the way for a gold standard of care for infertility treatment: improving outcomes through standardization of laboratory procedures
Infertility affects over 70 million couples globally. Access to, and interest in, assisted reproductive technologies is growing worldwide, with more couples seeking medical intervention to conceive, in particular by IVF. Despite numerous advances in IVF techniques since its first success in 1978, almost half of the patients treated remain childless. The multifactorial nature of IVF treatment means that success is dependent on many variables. Therefore, it is important to examine how each variable can be optimized to achieve the best possible outcomes for patients.Inositol supplementation in women with polycystic ovary syndrome undergoing intracytoplasmic sperm injection: a systematic review and meta-analysis of randomized controlled trials
Polycystic ovary syndrome (PCOS) is a complex and heterogeneous disease that involves menstrual dysfunction and reproductive difficulty, as well as metabolic problems. Use of the Rotterdam criteria will probably increase its already high prevalence, and currently, it is the most common endocrinopathy in women, affecting 7–14% of women of childbearing age worldwide (Bozdag et al., 2016).
